Tissue-mediated selection of viral variants: correlation between glycoprotein mutation and growth in neuronal cells.
Tissue-mediated selection of viral variants: correlation between glycoprotein mutation and growth in neuronal cells.
复制标题
组织介导的病毒变体选择：糖蛋白突变与神经元细胞生长之间的相关性。
DOI：
10.1128/jvi.68.11.7490-7496.1994
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发表时间：
1994
影响因子：
5.4
通讯作者：
Ahmed,R
中科院分区：
文献类型：
--
作者：
Villarete,L;Somasundaram,T;Ahmed,R
具有不同生物学特性的病毒变体在出生时感染阿姆斯特朗株淋巴细胞性脉络丛脑膜炎病毒的携带小鼠的中枢神经系统（CNS）和淋巴组织中占主导地位。CNS分离株具有与亲本菌株相同的表型，并在成年小鼠中引起急性感染，而脾来源的分离株引起与抑制的T细胞应答和对机会性感染的易感性相关的慢性感染。我们以前的研究已经确定了病毒糖蛋白中的单个氨基酸变化，即残基260处的苯丙氨酸至亮氨酸（F->L）突变，其与脾分离物的组织特异性选择和持久性和免疫抑制表型相关（R. Ahmed，C.S. Hahn，T.索马松达拉姆湖Villarete，M. Matloubian和J.H. Strauss，J. Virol. 65：4242-4247，1991）。在这项研究中，我们筛选了从脾，肝，肾，和大脑的载体小鼠的存在这种突变的病毒分离株，并确定了时间选择的变体，因为它们出现在这些器官。我们发现，这种F->L氨基酸变化在> 90%的脾和肝分离株中是常见的，并且在感染后（p.i.）32天迅速被选择。尽管在肾脏中观察到的动力学比在脾脏和肝脏中相对慢，但到感染后250天，这种F->L突变在肾脏来源的分离株中占主导地位。相比之下，大多数CNS分离株在感染后250天内保留亲本序列。此外，大多数脑分离物在神经元细胞系中有效复制，并且这种增强的神经元生长表型与亲本F基因型相关。这种与嗜神经性的联系，沿着我们早期的发现，即F-->L突变是增强巨噬细胞感染所必需的（M. Matloubian，S. R. Kolhekar，T. Somasundaram和R. Ahmed，J. Virol. 67：7340-7349，1993）提供了与组织特异性选择相关的分子变化的细胞基础。总而言之，这些结果表明，对巨噬细胞的嗜性是在脾脏和肝脏等组织中选择具有F-->L突变的变体的关键决定因素，而对神经元的嗜性对于在CNS中保留F基因型很重要。
Viral variants with different biological properties predominate in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the Armstrong strain of lymphocytic choriomeningitis virus. The CNS isolates have the same phenotype as the parental strain and cause acute infections in adult mice, while the spleen-derived isolates cause chronic infections associated with suppressed T-cell responses and susceptibility to opportunistic infections. Our previous studies have identified a single amino acid change in the viral glycoprotein, a phenylalanine-to-leucine (F-->L) mutation at residue 260, that correlates with the tissue-specific selection and the persistent and immunosuppressive phenotype of the spleen isolates (R. Ahmed, C.S. Hahn, T. Somasundaram, L. Villarete, M. Matloubian, and J. H. Strauss, J. Virol. 65:4242-4247, 1991). In this study, we screened viral isolates obtained from the spleen, liver, kidney, and brain of carrier mice for the presence of this mutation and determined the temporal selection of variants as they appear in these organs. We found that this F-->L amino acid change is common to > 90% of the spleen and liver isolates and is selected for rapidly by day 32 postinfection (p.i.). Although the kinetics observed in the kidney are relatively slower than in the spleen and liver, this F-->L mutation predominates in the kidney-derived isolates by 250 days p.i. In contrast, the majority of the CNS isolates retain the parental sequence up to 250 days p.i. In addition, most of the brain isolates replicated efficiently in a neuronal cell line, and this enhanced growth phenotype in neurons correlated with the parental F genotype. This linkage with neurotropism, along with our earlier finding that the F-->L mutation is necessary for enhanced infection of macrophages (M. Matloubian, S. R. Kolhekar, T. Somasundaram, and R. Ahmed, J. Virol. 67:7340-7349, 1993), provides a cellular basis for the molecular changes associated with tissue-specific selection. Taken together, these results suggest that tropism for macrophages is a critical determinant in selection of variants with the F-->L mutation in tissues such as spleen and liver, and tropism for neurons is important in retention of the F genotype in the CNS.